Phase II Study of Eribulin Mesylate, Trastuzumab, and Pertuzumab in Women With Metastatic, Unresectable Locally Advanced, or Locally Recurrent HER2-Positive Breast Cancer

NCT01912963 | Terminated Phase 2 Results DMC

• 1 other identifier: 13-163
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

Brief Summary

In this study, the investigators are testing the effectiveness of the combination of eribulin, pertuzumab and trastuzumab to learn whether this combination of drugs works in treating advanced HER2-positive breast cancer that had received at least one prior treatment previously. At this point, the standard treatment for HER2-positive cancer that has progressed (grown) after a first treatment is chemotherapy combined with therapies that target the HER2 protein (e.g., trastuzumab or lapatinib).

Conditions

HER2-positive Breast Cancer; Metastatic Breast Cancer

Keywords

HER-2 Positive Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Eribulin the Recommended Phase II Dose (RP2D) [Phase I]

  The RP2D of eribulin in combination with pertuzumab and trastuzumab is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The RP2D is defined as the highest dose at which fewer than one-third of six patients experience a DLT. In this Phase I run-in, only 2 dose levels were under evaluation: a starting dose (D1) and a de-escalation dose (D-1) if 2 or more DLTs are observed in Dose Level 1 (DL1).

  The observation period for the RP2D was the 1st cycle of treatment.

• Dose Limiting Toxicity (DLT) [Phase I]

  A DLT was defined as an adverse event that (a) is deemed by the investigator to be probably or likely related with protocol therapy and (b) occurs during and/or begins during the first cycle of the study treatment, and (c) meets any of the following criteria: grade 4 hematologic toxicity with \> 1 week of duration, grade 3 or 4 febrile neutropenia of any duration; or grade 3 or 4 non hematologic toxicity (excluding nausea, vomiting, and alopecia).

  The observation period for DLTs was the 1st cycle of treatment.

• Objective Response Rate (ORR) [Phase II]

  The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

  Disease was evaluated radiologically at baseline and every 2 or 3 cycles in the treatment and extension phase, respectively. Median (range) treatment duration was 7(2-25) cycles for Cohort A and 4(3-18) cycles for Cohort B.

Secondary Outcomes (4)

• Clinical Benefit Rate (CBR) [Phase II]

  Disease was evaluated radiologically at baseline and every 2 or 3 cycles in the treatment and extension phase, respectively. Median (range) treatment duration was 7(2-25) cycles for Cohort A and 4(3-18) cycles for Cohort B.

• Progression-free Survival (PFS) [Phase II]

  Disease was evaluated radiologically at baseline, every 2 or 3 cycles in the treatment and extension phase, respectively, and every 9 weeks post-treatment until disease progression. Median follow-up in this study cohort was 15.6 months (up to 20).

• Overall Survival (OS) [Phase II]

  In long-term follow-up, participants were followed for survival every 6 months up to 1 year after treatment discontinuation. Median follow-up in this study cohort was 15.6 months (up to 20).

• Grade 4 Treatment-Related Toxicity Rate

  AEs were assessed every cycle on treatment. Median (range) treatment duration was 7(2-25) cycles for Cohort A and 4(3-18) cycles for Cohort B.

Study Arms (3)

Phase I: Dose Level 1 (D1)

EXPERIMENTAL

Pertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (D1) Cycle duration=21 days The Phase I run-in potentially evaluates 2 dose levels of eribulin in combination with pertuzumab and trastuzumab. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.

Drug: Pertuzumab; Drug: Trastuzumab; Drug: eribulin

Phase II Cohort A: Without Prior Pertuzumab Exposure

EXPERIMENTAL

Pertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (recommended phase II dose) Cycle duration=21 days In the Phase II study, participants enrolled into two possible cohorts based on prior pertuzumab exposure. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.

Drug: Pertuzumab; Drug: Trastuzumab; Drug: eribulin

Phase II Cohort B: With Prior Pertuzumab Exposure

EXPERIMENTAL

Pertuzumab: 840 mg/cycle 1 then 420 mg/cycle IV on day 1 Trastuzumab: 8 mg/kg/cycle 1 then 6 mg/kg cycle IV on day 1 Eribulin: 1.4 mg/m2/cycle IV on days 1 and 8 (recommended phase II dose) Cycle duration=21 days In the Phase II study, participants enrolled into two possible cohorts based on prior pertuzumab exposure. Participants first receive antibody administration then eribulin. In the treatment phase, participants receive up to 6 cycles of combination therapy unless disease progression (PD) or withdrawal for other reasons (w/d). Participants who complete 6 cycles have the option to continue with antibody therapy only until PD or w/d in the extension phase.

Drug: Pertuzumab; Drug: Trastuzumab; Drug: eribulin

Interventions

Pertuzumab DRUG

Also known as: Perjeta

Phase I: Dose Level 1 (D1); Phase II Cohort A: Without Prior Pertuzumab Exposure; Phase II Cohort B: With Prior Pertuzumab Exposure

Trastuzumab DRUG

Also known as: Herceptin

Phase I: Dose Level 1 (D1); Phase II Cohort A: Without Prior Pertuzumab Exposure; Phase II Cohort B: With Prior Pertuzumab Exposure

eribulin DRUG

Also known as: eribulin mesylate, Halaven

Phase I: Dose Level 1 (D1); Phase II Cohort A: Without Prior Pertuzumab Exposure; Phase II Cohort B: With Prior Pertuzumab Exposure

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study:
• \- Participants must have invasive primary tumor or metastatic tissue confirmation of human epidermal growth factor receptor 2 (HER2)-positive status, defined as presence of one or more of the following criteria: Over-expression by immunohistochemistry (IHC) with score of 3+ AND/OR HER2 gene amplification (\> 6 HER2 gene copies per nucleus or a FISH ratio \[HER2 gene copies to chromosome 17 signals\] of ≥ 2.0) Note: Participants with a negative or equivocal overall result (FISH ratio of \<2.0 or ≤ 6.0 HER2 gene copies per nucleus) and IHC staining scores of 0, 1+, 2+ are not eligible for enrollment.
• Participants must have metastatic, unresectable locally advanced, or locally recurrent HER2-positive breast cancer. For the phase II portion of the study, it is required that participants have measurable disease, as defined by RECIST 1.1, which can be accurately evaluated on computerized tomography (CT) or magnetic resonance (MRI). Measurable disease is defined as: at least one lesion of \>10 mm in the longest diameter for a non-lymph node or \>15 mm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1.criteria.1
• Participants must have received at least 1 line of chemotherapy for advanced or metastatic breast cancer and/or relapse/progressed while on or within 6 months of completion of neoadjuvant or adjuvant trastuzumab. Prior pertuzumab is allowed in the phase II portion of the trial.
• Participants must have had prior trastuzumab therapy (either in the adjuvant or metastatic setting).
• Participants must be at least 2 weeks out from prior endocrine therapy, chemotherapy,radiotherapy, or other cancer-directed therapy (including novel agents), with adequate recovery of toxicity to baseline, or grade ≤1, with the exception of alopecia and hot flashes. Participants may have initiated bisphosphonate/denosumab therapy prior to start of protocol therapy. Biphosphonate/denosumab therapy may continue during protocol treatment. Such participants will have bone lesions considered evaluable for progression. Washout for trastuzumab is not necessary.
• Women and men, age 18 years at the time of informed consent.
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 or a Karnofsky Performance Scale (KP) 70%.
• Participants must have normal organ and marrow function as defined below:
• Absolute neutrophil count \> 1,500/mcL
• Platelets \> 75,000/mcL
• Hemoglobin \>9g/dl
• Total bilirubin ≤2.0 X institutional upper limit of normal
• Aspartate Aminotransferase (AST, SGOT)/ALT(Alanine Aminotransferase, SGPT) ≤ 3 X institutional ULN without liver metastases, or ≤ 5 times institutional upper limit normal (ULN) with liver metastases (if liver metastases felt to be cause of Liver function tests (LFT) abnormalities)
• Alkaline phosphatase (ALP) ≤3 x institutional upper limit of normal If total ALP is \>3x institutional upper limit normal (in the absence of liver metastasis) or \>5x institutional upper limit of normal (in subjects with liver metastasis) AND the subject is known to have bone metastases, then liver ALP isoenzyme should be used to assess liver function rather than total ALP.

You may not qualify if:

• Participants receiving any other study agents.
• Participants receiving any other cancer directed concurrent therapy; such as concurrent chemotherapy, radiotherapy, or hormonal therapy. Concurrent treatment with biphosphonates/denosumab is allowed but should be started before starting treatment on study.
• Active brain metastases: Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to enrollment, are neurologically stable, and have recovery from effects of radiotherapy or surgery.
• History of allergic reaction attributed to compounds of similar chemical or biologic composition to eribulin mesylate, trastuzumab or pertuzumab, which cannot be managed by premedication.
• Participants who previously received eribulin mesylate are not eligible for enrollment on the phase II portion.
• Prior chemotherapy, targeted therapy, hormonal therapy, or radiation therapy (including any investigational agents) within 2 weeks prior entering the study or those who have not recovered adequately from adverse events (AEs) due to agents administered more than 4 weeks earlier (excluding alopecia and hot flashes). A washout period is not necessary for trastuzumab (or pertuzumab for run-in patients when applicable).
• A baseline corrected QT interval of \> 470 ms.
• Pre-existing neuropathy ≥ grade 2 (NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.0)
• Uncontrolled intercurrent illness including, not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or other significant diseases or disorders that, in the investigator's opinion, would exclude the subject from participating in the study
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in grade 2 or higher dyspnea at rest.
• Currently pregnant or breast-feeding. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of β-Human Chorionic Gonadotropin (β-Hcg) at the Baseline visit \[within 7 days of the first dose of study treatment\]). Females of childbearing potential must agree to use a medically acceptable method of contraception (e.g., abstinence, an intrauterine device, a double-barrier method such as condom + spermicidal or condom + diaphragm with spermicidal, a contraceptive implant, an oral contraceptive or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after discontinuation of study treatment. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month before start of study treatment, hysterectomy, or bilateral oophorectomy with surgery at least 1 month before start of study treatment). Current, ongoing protocols containing pertuzumab have included continuous pregnancy monitoring during the trial and for six months after the last dose of study drug is administered. Because of the long half-life of pertuzumab, women should be warned not to become pregnant for at least six months after completion of treatment.
• Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Eisai Inc.: collaborator
• Genentech, Inc.: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Balch SM, Vaz-Luis I, Li T, Tayob N, Jain E, Helvie K, Buendia-Buendia JE, Shannon E, Isakoff SJ, Tung NM, Krop IE, Lin NU, Wagle N, Freedman RA. A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. Breast Cancer Res Treat. 2021 Sep;189(2):411-423. doi: 10.1007/s10549-021-06329-x. Epub 2021 Jul 24.

  PMID: 34302589 DERIVED

Related Links

• American Society Clinical Oncology (ASCO) 2017 abstract

MeSH Terms

Conditions

Breast Neoplasms

Interventions

pertuzumab; Trastuzumab; eribulin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study is limited as it was terminated early due to slow accrual.

Results Point of Contact

• Title: Rachel Freeman MD
• Organization: Dana-Farber Cancer Institute

Rachel_Freedman@dfci.harvard.edu

617.632.3000

Study Officials

• Rachel Freedman, MD, MPH

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Of note, this is not a parallel assignment rather one Phase I arm and two Phase II arms all independently evaluated.

Study Record Dates

• First Submitted: July 24, 2013
• First Posted: July 31, 2013
• Study Start: September 1, 2013
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: December 5, 2018
• Results First Posted: December 5, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)